Gastrointestinal Characteristics of Constipation from the Perspectives of Microbiome and Metabolome.

BACKGROUND: Constipation is one of the most common gastrointestinal complaints. Yet, the underlying mechanisms of constipation remain to be explored deeply. Integration of microbiome and metabolome is powerful and promising to demonstrate characteristics of constipation. AIM OF STUDY: This study aimed to characterize intestinal microbiome and metabolome of constipation. In addition, this study revealed the correlations among behaviors, intestinal microbiota, and metabolites interrupted by constipation. METHODS: Firstly, the constipation model was successfully applied. At the macro level, the ability of learning, memory, locomotor activity, and the defecation index of rats with constipation-like phenotype were characterized. At the micro-level, 16S rRNA sequencing was applied to analyze the intestinal microbiota in rats with constipation-like phenotype. 1H nuclear magnetic resonance (NMR)-based metabolomics was employed to investigate the metabolic phenotype of constipation. In addition, we constructed a correlation network, intuitively showing the correlations among behaviors, intestinal microbiota, and metabolites. RESULTS: Constipation significantly attenuated the locomotor activity, memory recognition, and frequency of defecation of rats, while increased the time of defecation. Constipation significantly changed the diversity of intestinal microbial communities, which correspondingly involved in 5 functional pathways. Besides, 28 fecal metabolites were found to be associated with constipation, among which 14 metabolites were further screened that can be used to diagnose constipation. On top of this, associated networks intuitively showed the correlations among behaviors, intestinal microbiota, and metabolites. CONCLUSIONS: The current findings are significant in terms of not only laying a foundation for understanding characteristics of constipation, but also providing accurate diagnosis and treatments of constipation clinically.

Structure characterization of polysaccharides from Cistanche deserticola and their neuroprotective effects against oxidative stress in slow transit constipation mice.

Oxidative stress-induced enteric neuropathy is an important factor in slow transit constipation (STC). Cistanche deserticola crude polysaccharides (CDCP) are natural antioxidants with various biological activities. We prepared CDCP through water-extract and alcohol-precipitation methods. The structural characteristics of CDCP were analyzed by infrared spectroscopy and methylation analysis. The results showed that CDCP was primarily composed of (1 â†’ 4)-linked glucans with minor amounts of pectic polysaccharides. Different doses of CDCP (100, 200, and 400 mg/kg) were administered to loperamide-induced STC mice to explore the therapeutic effects of CDCP. Compared with the untreated group, CDCP treatment significantly improved constipation symptoms, relevant gut-regulating peptides levels, colonic pathological damage, and colonic myenteric nerons injury. CDCP enhanced the antioxidant capacity by decreasing Malondialdehyde (MDA) content, increasing Superoxide Dismutase (SOD) activity and Reduced Glutathione (GSH) content. CDCP significantly reduced oxidative stress-induced injury by preserving mitochondrial function in the colonic myenteric plexus. Furthermore, the neuroprotective effects of CDCP might be associated with the Nrf2/Keap1 pathway. Thus, our findings first revealed the potential of CDCP to protect the colonic myenteric plexus against oxidative stress-induced damage in STC, establishing CDCP as promising candidates for natural medicine in the clinical management of STC.

Torreya grandis Kernel Oil Alleviates Loperamide-Induced Slow Transit Constipation via Up-Regulating the Colonic Expressions of Occludin/Claudin-1/ZO-1 and 5-HT3R/5-HT4R in BALB/c Mice.

SCOPE: Torreya grandis kernel has traditionally been used to remove intestinal parasites and increases intestinal motility. However, the effect of Torreya grandis kernel oil (TKO) on constipation has not yet been investigated. Therefore, mouse model is used to investigate the effect of TKO on slow transit constipation (STC) and its possible mechanism. METHODS AND RESULTS: The effects of TKO on intestinal motility of STC mice are evaluated by fecal weight, fecal water content, colon length, defecation test, and intestinal propulsion test. The mechanism of TKO alleviating STC is explored by detecting biochemical analysis, histological analysis, western blot, qRT-PCR, immunohistochemistry, and gut microbiota analysis. The results reveal that TKO effectively promotes defecation and intestinal motility, increases the level of endothelin-1, and restores the histopathological morphology of the colon under LOP pretreatment. The expression levels of occludin, claudin-1, and zonula occludens-1 (ZO-1) mRNA and protein are up-regulated in mice receiving TKO treatment. The colonic 5-hydroxytryptamine 3R/4R (5-HT3R/5-HT4R) expressions are also increased by TKO supplementation. Additionally, TKO rescues LOP-caused disorders of the gut microbiota. CONCLUSION: Consumption of TKO is beneficial to STC recovery, and it can alleviate LOP-induced STC by up-regulating the colonic expressions of Occludin/Claudin-1/ZO-1 and 5-HT3R/5-HT4R.

Rhubarb extract rebuilding the mucus homeostasis and regulating mucin-associated flora to relieve constipation.

In clinical trials, rhubarb extract (Rb) was demonstrated to efficiently alleviate constipation. We would like to find out the underlying mechanism of rhubarb relieving constipation. However, there are few studies on the effects of rhubarb on colonic mucus secretion and constipation. The aim of this study was to investigate the effects of rhubarb on colonic mucus secretion and its underlying mechanism. The mice were randomly divided into four groups. Group I was the control group and Group II was the rhubarb control group, with Rb (24 g/kg body weight [b.w.]) administered through intragastric administration for three days. Group III mice were given diphenoxylate (20 mg/kg b.w.) for five days via gavage to induce constipation. Group IV received diphenoxylate lasting five days before undergoing Rb administration for three days. The condition of the colon was evaluated using an endoscope. Particularly, the diameter of blood vessels in the colonic mucosa expanded considerably in constipation mice along with diminishing mucus output, which was in line with the observation via scanning electron microscope (SEM) and transmission electron microscope (TEM). We also performed metagenomic analysis to reveal the microbiome related to mucin gene expression level referring to mucin secretion. In conclusion, Rb relieves constipation by rebuilding mucus homeostasis and regulating the microbiome.

Insights into the Current and Possible Future Use of Opioid Antagonists in Relation to Opioid-Induced Constipation and Dysbiosis.

Opioid receptor agonists, particularly those that activate µ-opioid receptors (MORs), are essential analgesic agents for acute or chronic mild to severe pain treatment. However, their use has raised concerns including, among others, intestinal dysbiosis. In addition, growing data on constipation-evoked intestinal dysbiosis have been reported. Opioid-induced constipation (OIC) creates an obstacle to continuing treatment with opioid analgesics. When non-opioid therapies fail to overcome the OIC, opioid antagonists with peripheral, fast first-pass metabolism, and gastrointestinal localized effects remain the drug of choice for OIC, which are discussed here. At first glance, their use seems to only be restricted to constipation, however, recent data on OIC-related dysbiosis and its contribution to the appearance of several opioid side effects has garnered a great of attention from researchers. Peripheral MORs have also been considered as a future target for opioid analgesics with limited central side effects. The properties of MOR antagonists counteracting OIC, and with limited influence on central and possibly peripheral MOR-mediated antinociception, will be highlighted. A new concept is also proposed for developing gut-selective MOR antagonists to treat or restore OIC while keeping peripheral antinociception unaffected. The impact of opioid antagonists on OIC in relation to changes in the gut microbiome is included.

The substantia nigra modulates proximal colon tone and motility in a vagally-dependent manner in the rat.

A monosynaptic pathway connects the substantia nigra pars compacta (SNpc) to neurons of the dorsal motor nucleus of the vagus (DMV). This monosynaptic pathway modulates the vagal control of gastric motility. It is not known, however, whether this nigro-vagal pathway also modulates the tone and motility of the proximal colon. In rats, microinjection of retrograde tracers in the proximal colon and of anterograde tracers in SNpc showed that bilaterally labelled colonic-projecting neurons in the DMV received inputs from SNpc neurons. Microinjections of the ionotropic glutamate receptor agonist, NMDA, in the SNpc increased proximal colonic motility and tone, as measured via a strain gauge aligned with the colonic circular smooth muscle; the motility increase was inhibited by acute subdiaphragmatic vagotomy. Upon transfection of SNpc with pAAV-hSyn-hM3D(Gq)-mCherry, chemogenetic activation of nigro-vagal nerve terminals by brainstem application of clozapine-N-oxide increased the firing rate of DMV neurons and proximal colon motility; both responses were abolished by brainstem pretreatment with the dopaminergic D1-like antagonist SCH23390. Chemogenetic inhibition of nigro-vagal nerve terminals following SNpc transfection with pAAV-hSyn-hM4D(Gi)-mCherry decreased the firing rate of DMV neurons and inhibited proximal colon motility. These data suggest that a nigro-vagal pathway modulates activity of the proximal colon motility tonically via a discrete dopaminergic synapse in a manner dependent on vagal efferent nerve activity. Impairment of this nigro-vagal pathway may contribute to the severely reduced colonic transit and prominent constipation observed in both patients and animal models of parkinsonism. KEY POINTS: Substantia nigra pars compacta (SNpc) neurons are connected to the dorsal motor nucleus of the vagus (DMV) neurons via a presumed direct pathway. Brainstem neurons in the lateral DMV innervate the proximal colon. Colonic-projecting DMV neurons receive inputs from neurons of the SNpc. The nigro-vagal pathway modulates tone and motility of the proximal colon via D1-like receptors in the DMV. The present study provides the mechanistic basis for explaining how SNpc alterations may lead to a high rate of constipation in patients with Parkinson's Disease.

Ligand-Modified Gold Nanoparticles as Mitochondrial Modulators: Regulation of Intestinal Barrier and Therapy for Constipation.

Intestinal metabolism-related diseases, such as constipation, inflammatory bowel disease, irritable bowel syndrome, and colorectal cancer, could be associated with the dysfunction of intestinal mitochondria. The mitochondria of intestinal epithelial cells are of great significance for promoting intestinal motility and maintaining intestinal metabolism. It is necessary for the prophylaxis and therapy of intestinal metabolism-related diseases to improve mitochondrial function. We investigated the effect of 4,6-diamino-2-pyrimidinethiol-modified gold nanoparticles (D-Au NPs) on intestinal mitochondria and studied the regulatory role of D-Au NPs on mitochondria metabolism-related disease. D-Au NPs improved the antioxidation capability of mitochondria, regulated the mitochondrial metabolism, and maintained intestinal cellular homeostasis via the activation of AMPK and regulation of PGC-1α with its downstream signaling (UCP2 and DRP1), enhancing the intestinal mechanical barrier. D-Au NPs improved the intestinal mitochondrial function to intervene in the emergence of constipation, which could help develop drugs to treat and prevent mitochondrial metabolism-related diseases. Our findings provided an in-depth understanding of the mitochondrial effects of Au NPs for improving human intestinal barriers.

Mini-review: Enteric glial cell reactions to inflammation and potential therapeutic implications for GI diseases, motility disorders, and abdominal pain.

Enteric glial cells are emerging as critical players in the regulation of intestinal motility, secretion, epithelial barrier function, and gut homeostasis in health and disease. Enteric glia react to intestinal inflammation by converting to a 'reactive glial phenotype' and enteric gliosis, contributing to neuroinflammation, enteric neuropathy, bowel motor dysfunction and dysmotility, diarrhea or constipation, 'leaky gut', and visceral pain. The focus of the minireview is on the impact of inflammation on enteric glia reactivity in response to diverse insults such as intestinal surgery, ischemia, infections (C. difficile infection, HIV-Tat-induced diarrhea, endotoxemia and paralytic ileus), GI diseases (inflammatory bowel diseases, diverticular disease, necrotizing enterocolitis, colorectal cancer) and functional GI disorders (postoperative ileus, chronic intestinal pseudo-obstruction, constipation, irritable bowel syndrome). Significant progress has been made in recent years on molecular pathogenic mechanisms of glial reactivity and enteric gliosis, resulting in enteric neuropathy, disruption of motility, diarrhea, visceral hypersensitivity and abdominal pain. There is a growing number of glial molecular targets with therapeutic implications that includes receptors for interleukin-1 (IL-1R), purines (P2X2R, A2BR), PPARα, lysophosphatidic acid (LPAR1), Toll-like receptor 4 (TLR4R), estrogen-ß receptor (ERß) adrenergic α-2 (α-2R) and endothelin B (ETBR), connexin-43 / Colony-stimulating factor 1 signaling (Cx43/CSF1) and the S100ß/RAGE signaling pathway. These exciting new developments are the subject of the minireview. Some of the findings in pre-clinical models may be translatable to humans, raising the possibility of designing future clinical trials to test therapeutic application(s). Overall, research on enteric glia has resulted in significant advances in our understanding of GI pathophysiology.

Apple juice relieves loperamide-induced constipation in rats by downregulating the intestinal apical sodium-dependent bile acid transporter ASBT.

Apples are known to exhibit various beneficial effects on human health. In the present study, we investigated the effect of continuous intake of apple juice (AJ) on constipation status. A single dose of loperamide in rats as the constipation model markedly decreased the weight and number of fecal pellets compared to saline-administered rats as a control. After the administration of AJ twice a day for seven days, recovery of defecation close to that of the control was observed in loperamide-treated rats. In addition, the total bile acid content in the feces increased from day 4 after the administration of AJ. Among hepatic and intestinal transporters and enzymes that regulate bile acids, the mRNA expression of the apical sodium-dependent bile acid transporter (Asbt, slc10a2) was decreased by AJ in rats. Furthermore, the Asbt-mediated bile acid transport activity in the rat ileum decreased after AJ administration. Moreover, in human colonic cancer-derived Caco-2 cells, AJ exposure for 24 and 48 h decreased the expressions of ASBT mRNA and protein, and the uptake activity of taurocholic acid in both 7- and 21-d cultures. Several components of AJ, such as procyanidins, decreased the expression of ASBT in Caco-2 cells. In conclusion, ASBT downregulation is a possible mechanism responsible for the constipation-relieving effect of apples, and procyanidins may play a role in downregulating ASBT, which leads to the beneficial effects of apples against constipation. Although it is generally agreed that the common dietary compositions play a role in constipation relief, the novel specific mechanism of apples found in this study would facilitate understanding food functions.

Flavonoids in Amomum tsaoko Crevost et Lemarie Ameliorate Loperamide-Induced Constipation in Mice by Regulating Gut Microbiota and Related Metabolites.

Amomum tsaoko (AT) is a dietary botanical with laxative properties; however, the active ingredients and mechanisms are still unclear. The active fraction of AT aqueous extract (ATAE) for promoting defecation in slow transit constipation mice is the ethanol-soluble part (ATES). The total flavonoids of ATES (ATTF) were the main active component. ATTF significantly increased the abundance of Lactobacillus and Bacillus and reduced the dominant commensals, such as Lachnospiraceae, thereby changing the gut microbiota structure and composition. Meanwhile, ATTF changed the gut metabolites mainly enriched in pathways such as the serotonergic synapse. In addition, ATTF increased the serum serotonin (5-HT) content and mRNA expression of 5-hydroxytryptamine receptor 2A (5-HT2A), Phospholipase A2 (PLA2), and Cyclooxygenase-2 (COX2), which are involved in the serotonergic synaptic pathway. ATTF increased Transient receptor potential A1 (TRPA1), which promotes the release of 5-HT, and Myosin light chain 3(MLC3), which promotes smooth muscle motility. Notably, we established a network between gut microbiota, gut metabolites, and host parameters. The dominant gut microbiota Lactobacillus and Bacillus, prostaglandin J2 (PGJ2) and laxative phenotypes showed the most significant associations. The above results suggest that ATTF may relieve constipation by regulating the gut microbiota and serotonergic synaptic pathway and has great potential for laxative drug development in the future.

Integrating omics and network pharmacology reveals the anti-constipation role of chitosan with different molecular weights in constipated mice.

This study aimed to reveal the constipation-relieving role of chitosan (COS) with different molecular weights (1 kDa, 3 kDa and 244 kDa). Compared with COS3K (3 kDa) and COS240K (244 kDa), COS1K (1 kDa) more significantly accelerated gastrointestinal transit and defecation frequency. These differential effects were reflected in the regulation of specific gut microbiota (Desulfovibrio, Bacteroides, Parabacteroides and Anaerovorax) and short-chain fatty acids (propionic acid, butyric acid and valeric acid). RNA-sequencing found that the differential expressed genes (DEGs) caused by different molecular weights of COS were mainly enriched in intestinal immune-related pathways, especially cell adhesion molecules. Furthermore, network pharmacology revealed two candidate genes (Clu and Igf2), which can be regarded as the key molecules for the differential anti-constipation effects of COS with different molecular weights. These results were further verified by qPCR. In conclusion, our results provide a novel research strategy to help understand the differences in the anti-constipation effects of chitosan with different molecular weights.

A. macrocephala polysaccharide induces alterations to gut microbiome and serum metabolome in constipated mice.

Atractylodes macrocephala polysaccharide (AC1) is extracted from the root of the Chinese herb Atractylodes Macrocephala and is used in the treatment of constipation due to its effects on strengthening cellular immunity and regulating intestinal function. In this study, Metagenomics and Metabolomic are used to analyze the effects of AC1 on the gut microbiota and host metabolites in mice models of constipation. The results show that the abundance of Lachnospiraceae_bacterium_A4, Bact-oides_vulgatus and Prevotella_sp_CAG:891 increased significantly, indicating that AC1-targeted strain modulation effectively alleviated the dysbiosis of the gut microbiota. Besides, the microbial alterations also influenced the metabolic pathways of the mice, including tryptophan metabolism, unsaturated fatty acid synthesis and bile acid metabolism. The physiological parameters of the mice treated with AC1 are improved, such as tryptophan in the colon, 5-hydroxytryptamine (5-HT) and short-chain fatty acids (SCFAs). In conclusion, AC1 as a probiotic can regulate intestinal flora to normal levels and achieve the effect of treating constipation.

Improvement of loperamide-hydrochloride-induced intestinal motility disturbance by Platycodon grandiflorum polysaccharides through effects on gut microbes and colonic serotonin.

Constipation is a common gastrointestinal symptom characterized by intestinal motility disorder. The effects of Platycodon grandiflorum polysaccharides (PGP) on intestinal motility have not been confirmed. We established a rat model of constipation induced by loperamide hydrochloride to elucidate the therapeutic effect of PGP on intestinal motility disorder and to explore the possible mechanism. After PGP treatment (400 and 800 mg/kg) for 21 d, PGP clearly relieved gastrointestinal motility, including fecal water content, gastric emptying rate, and intestinal transit rate. Moreover, the secretion of motility-related hormones, gastrin and motilin, were increased. Enzyme-linked immunosorbent assay, western blot, immunohistochemistry, and immunofluorescence results confirmed that PGP significantly increased the secretion of 5-hydroxytryptamine (5-HT) and the expression of related proteins, such as tryptophan hydroxylase 1, 5-HT4 receptor, and transient receptor potential ankyrin 1. 16S rRNA gene sequencing showed that PGP significantly increased the relative abundance of Roseburia, Butyricimonas, and Ruminiclostridium, which were positively correlated with 5-HT levels. However, the relative abundance of Clostridia_UCG-014, Lactobacillus, and Enterococcus were decreased. PGP improved intestinal transport by regulating the levels of 5-HT, which interacts with the gut microbiota and the intestinal neuro-endocrine system, further affecting constipation. Overall, PGP is a potential supplement for the treatment of constipation.

Fu Brick Tea Alleviates Constipation via Regulating the Aquaporins-Mediated Water Transport System in Association with Gut Microbiota.

This study aimed to investigate the amendatory effects of Fu brick tea aqueous extract (FTE) on constipation and its underlying molecular mechanism. The administration of FTE by oral gavage (100 and 400 mg/kg·bw) for 5 weeks significantly increased fecal water content, improved difficult defecation, and enhanced intestinal propulsion in loperamide (LOP)-induced constipated mice. FTE also reduced colonic inflammatory factors, maintained the intestinal tight junction structure, and inhibited colonic Aquaporins (AQPs) expression, thus normalizing the intestinal barrier and colonic water transport system of constipated mice. 16S rRNA gene sequence analysis results indicated that two doses of FTE increased the Firmicutes/Bacteroidota (F/B) ratio at the phylum level and increased the relative abundance of Lactobacillus from 5.6 ± 1.3 to 21.5 ± 3.4% and 28.5 ± 4.3% at the genus level, subsequently resulting in a significant elevation of colonic contents short-chain fatty acids levels. The metabolomic analysis demonstrated that FTE improved levels of 25 metabolites associated with constipation. These findings suggest that Fu brick tea has the potential to alleviate constipation by regulating gut microbiota and its metabolites, thereby improving the intestinal barrier and AQPs-mediated water transport system in mice.

Serum Metabolic Profile in Schizophrenia Patients With Antipsychotic-Induced Constipation and Its relationship With Gut Microbiome.

BACKGROUND AND HYPOTHESIS: Antipsychotics (APs), the cornerstone of schizophrenia treatment, confer a relatively high risk of constipation. However, the mechanisms underpinning AP-induced constipation are poorly understood. Thus, we hypothesized that (1) schizophrenia patients with AP-induced constipation have distinct metabolic patterns; (2) there is more than one mechanism at play in producing this adverse drug effect; and (3) AP-associated changes in the gut microbiome are related to the altered metabolic profiles. STUDY DESIGN: Eighty-eight schizophrenia patients, including 44 with constipation (C) and 44 matched patients without constipation (NC), were enrolled in this study. Constipation was diagnosed by Rome IV criteria for constipation and colonic transit time using radiopaque markers (ROMs) while severity was evaluated with the Bristol Stool Form Scale (BSS) and Constipation Assessment Scale (CAS). Fasting blood samples were drawn from all participants and were subjected to non-targeted liquid chromatography-mass spectrometry (LC-MS) metabolomic analysis. STUDY RESULTS: Eleven metabolites were significantly altered in AP-induced constipation which primarily disturbed sphingolipid metabolism, choline metabolism, and sphingolipid signaling pathway (P value < .05, FDR < 0.05). In the C group, changes in the gut bacteria showed a certain degree of correlation with 2 of the significantly altered serum metabolites and were associated with alterations in choline metabolism. CONCLUSIONS: Our findings indicated that there were disturbances in distinct metabolic pathways that were associated with AP-induced constipation. In addition, this study presents evidence of a link between alterations in the gut microbiome and host metabolism which provides additional mechanistic insights on AP-induced constipation.

Impaired Intestinal Permeability of Tricellular Tight Junctions in Patients with Irritable Bowel Syndrome with Mixed Bowel Habits (IBS-M).

BACKGROUND: The underlying pathophysiology of irritable bowel syndrome (IBS) is still unclear. Our aim was to investigate the pathophysiological mechanisms of diarrhea, constipation, and antigen uptake in mixed-type IBS (IBS-M). METHODS: Colonoscopic biopsies were obtained from IBS-M patients. Epithelial transport and barrier function of colonic mucosae were characterized in Ussing chambers using impedance spectroscopy. Mucosal permeability to macromolecules was measured. Western blotting for tight junction (TJ) proteins was performed and their subcellular localization was visualized by confocal microscopy. RNA-sequencing was performed for gene expression and signaling pathway analysis. RESULTS: In IBS-M, epithelial resistance and ENaC-dependent sodium absorption were unchanged, while short-circuit current reflecting chloride secretion was reduced. Concomitantly, epithelial permeability for fluorescein and FITC-dextran-4000 increased. TJ protein expression of occludin decreased, whereas claudins were unaltered. Confocal microscopy revealed the de-localization of tricellulin from tricellular TJs. Involved pathways were detected as proinflammatory cytokine pathways, LPS, PGE2, NGF, and vitamin D. CONCLUSIONS: Decreased anion secretion explains constipation in IBS-M, while ion permeability and sodium absorption were unaltered. Reduced occludin expression resulted in the delocalization of tricellulin from the tricellular TJ, leading to increased macromolecular permeability that contributes to antigen influx into the mucosa and perpetuates a low-grade inflammatory process.

Effect and mechanism of functional compound fruit drink on gut microbiota in constipation mice.

Compound fruit drink (CFD) is a functional drink prepared with fruit, Chinese herbs and prebiotic fructooligosaccharide as the main ingredients. Loperamide hydrochloride was used to establish a mouse model of constipation. And the effect of CFD on the improvement of constipation and the impact on gut microbiota were studied. The results showed that CFD significantly enhanced intestinal motility in constipated mice (P < 0.05). It significantly improved serum levels of gastrointestinal regulatory-related peptides, elevated the short-chain fatty acids (SCFAs) content and alleviated colonic injury. Meanwhile, CFD also up-regulated the mRNA expression levels of AQP3, AQP9, SCF and c-Kit and the related protein expression levels. Fecal microbial results showed that the CFD medium-dose group significantly increased species richness. Furthermore, CFD increased the abundance of potentially beneficial bacteria and reduced the number of potentially pathogenic bacteria. This study indicated that CFD was a promising functional drink for effectively relieving constipation.

Zhizhu decoction alleviates slow transit constipation by regulating aryl hydrocarbon receptor through gut microbiota.

CONTEXT: Slow transit constipation (STC), the most common type of constipation, seriously affects the life of patients. Zhizhu decoction (ZZD), a traditional Chinese medicine compound, has is effective against functional constipation, but the mechanism is still unclear. OBJECTIVE: This research explores the mechanism of ZZD on STC from the perspective of metabolomics and gut microbiota. MATERIALS AND METHODS: Fifty-four C57BL/6 mice were randomly divided into six groups (n = 9): control (control); STC (model); positive control (positive); low-dose (5 g/kg; L-ZZD), medium-dose (10 g/kg; M-ZZD), and high-dose (20 g/kg; H-ZZD) ZZD treatment. Following treatment of mice with ZZD for two weeks, the changes in intestinal motility, colon histology, intestinal neurotransmitters, and aryl hydrocarbon receptor (AHR) pathway determined the effects of ZZD on the pathophysiology of STC. LC-MS targeting serum metabolomics was used to analyze the regulation of ZZD on neurotransmitters, and 16S rRNA high-throughput sequencing was used to detect the regulation of the gut microbiome. RESULTS: ZZD had the highest content of naringin (6348.1 mg/L), and could significantly increase the 24 h defecations (1.10- to 1.42-fold), fecal moisture (1.14-fold) and intestinal transport rate (1.28-fold) of STC mice, increased the thickness of the mucosal and muscular tissue (1.18- to 2.16-fold) and regulated the neurotransmitters in the colon of STC mice. Moreover, ZZD significantly activated the AHR signaling pathway, and also affected the composition of gut microbiota in STC mice. DISCUSSION AND CONCLUSIONS: The beneficial effect and the possible mechanism of ZZD on STC could provide a theoretical basis for the broader clinical application of ZZD.

Astragalus Polysaccharide Alleviates Constipation in the Elderly Via Modification of Gut Microbiota and Fecal Metabolism.

Constipation is one of the most common gastrointestinal disorders, whose incidence increasing with age. As one of the main components, Astragalus polysaccharide (APS) has been used to treat a variety of diseases. This study aimed to explore the effects of APS on the improvement of gastrointestinal functions and learning memory in elderly rats with constipation. In this study, both 16S rRNA sequencing-based microbiome and 1H NMR-based metabolomics were applied to demonstrate the effects of APS on host metabolism and gut microbiota of the elderly rats with constipation. On top of this, we constructed both inter- and inner-layer networks, intuitively showing the correlations among behavioral indicators, intestinal bacteria, and differential metabolites. Our results showed that APS significantly ameliorated the constipation and the cognitive dysfunctions of rats. Microbiome analysis revealed that APS raised the relative abundance of Blautia, whereas decreased the relative abundance of Lactobacillus in the elderly rats with constipation. In addition, APS decreased the levels of acetate, butyrate, and propionate in the fecal samples, correspondingly regulating glycolysis/gluconeogenesis metabolism and pyruvate metabolism. These findings lay solid foundations for understanding the pathogenesis of constipation in the elderly, and also offer a promising new treatment strategy for constipation in the elderly.

Gut microbiota: a new avenue to reveal pathological mechanisms of constipation.

Constipation is very pervasive all over the world. It is a common multifactorial gastrointestinal disease, and its etiology and pathomechanism are not completely clear. Now, increasing evidence shows that intestinal flora is closely related to constipation. Intestinal flora is the largest microbiota in the human body and has powerful metabolic functions. Intestinal flora can produce a variety of metabolites, such as bile acids, short-chain fatty acids, tryptophan metabolites, and methane, which have important effects on intestinal motility and secretion. The host can also monitor the intestinal flora and regulate gut dysbacteriosis in constipation. To explore the relationship between intestinal flora and host, the combination of multiomics technology has become the powerful and effective method. Furthermore, the homeostasis restoration of intestinal flora also provides a new strategy for the treatment of constipation. This review aims to explore the interaction between intestinal flora and host in constipation, which contributes to disclose the pathogenesis of constipation and the development of novel drugs for the treatment of constipation from the perspective of intestinal flora. KEY POINTS: • This review highlights the regulation of gut microbiota on the intestinal motility and secretion of host. • The current review gives an insight into the role of the host on the recognition and regulation of intestinal ecology under constipation. • The article also introduces some novel methods of current gut microbiota research and gut microbiota-based constipation therapies.